β3-Adrenoceptor Impairs Mitochondrial Biogenesis and Energy Metabolism During Rapid Atrial Pacing-Induced Atrial Fibrillation

被引：44

作者：

Dong, Jingmei ^{[1
]}

Zhao, Jingjing ^{[1
]}

Zhang, Miaomiao ^{[1
]}

Liu, Guangzhong ^{[1
]}

Wang, Xiaobing ^{[1
]}

Liu, Yixi ^{[1
]}

Yang, Ning ^{[2
]}

Liu, Yongwu ^{[3
]}

Zhao, Guanqi ^{[1
]}

Sun, Jiayu ^{[1
]}

Tian, Jingpu ^{[1
]}

Cheng, Cheping ^{[4
]}

Wei, Lin ^{[5
]}

Li, Yue ^{[1
]}

Li, Weimin ^{[1
]}

机构：

[1] Harbin Med Univ, Affiliated Hosp 1, Dept Cardiol, Harbin 150001, Heilongjiang, Peoples R China

[2] Harbin Med Univ, Affiliated Hosp 1, Harbin 150001, Heilongjiang, Peoples R China

[3] Heilongjiang Univ Chinese Med, Ctr Drug Safety Evaluat, Harbin, Peoples R China

[4] Wake Forest Univ, Dept Cardiol, Sch Med, Winston Salem, NC 27109 USA

[5] First Hosp Harbin City, Dept Cardiol, Harbin, Peoples R China

来源：

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS | 2016年 / 21卷 / 01期

基金：

中国国家自然科学基金;

关键词：

atrial fibrillation; 3-adrenoceptor; metabolic remodeling; mitochondrial biogenesis; UP-REGULATION; MYOCARDIAL-INFARCTION; SKELETAL-MUSCLE; ADIPOSE-TISSUE; HEART-FAILURE; CANINE MODEL; ACTIVATION; STIMULATION; BETA(3)-ADRENOCEPTOR; TRANSCRIPTION;

D O I：

10.1177/1074248415590440

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Background: The 3-adrenoceptor (3-AR) is implicated in cardiac remodeling. Since metabolic dysfunction due to loss of mitochondria plays an important role in heart diseases, we examined the effects of 3-AR on mitochondrial biogenesis and energy metabolism in atrial fibrillation (AF). Methods: Atrial fibrillation was created by rapid atrial pacing in adult rabbits. Rabbits were randomly divided into 4 groups: control, pacing (P7), 3-AR antagonist (L748337), and 3-AR agonist (BRL37344) groups. Atrial effective refractory period (AERP) and AF induction rate were measured. Atrial concentrations of adenine nucleotides and phosphocreatine were quantified through high-performance liquid chromatography. Mitochondrial DNA content was determined. Real-time polymerase chain reaction and Western blot were used to examine the expression levels of signaling intermediates related to mitochondrial biogenesis. Results: After pacing for 7 days, 3-AR was significantly upregulated, AERP was reduced, and the AF induction rate was increased. The total adenine nucleotides pool was significantly reduced due to the decrease in adenosine triphosphate (ATP). The P7 group showed decreased activity of F0F1-ATPase. Mitochondrial DNA content was decreased and mitochondrial respiratory chain subunits were downregulated after pacing. Furthermore, expression of transcription factors involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor coactivator 1 (PGC-1), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (Tfam), was lower in the P7 group in response to 3-AR activation. Further stimulation of 3-AR with BRL37344 exacerbated these effects, together with a significant decrease in the levels of phosphocreatine. In contrast, inhibition of 3-AR with L748337 partially restored mitochondrial biogenesis and energy metabolism of atria in the paced rabbits. Conclusion: The activation of 3-AR contributes to atrial metabolic remodeling via transcriptional downregulation of PGC-1/NRF-1/Tfam pathway that are involved in mitochondrial biogenesis, which ultimately perturbs mitochondrial function in rapid pacing-induced AF. The 3-AR is therefore a potential novel therapeutic target for the treatment or prevention of AF.

引用

页码：114 / 126

页数：13

共 59 条

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